What is the appropriate dosing, indications, and safety monitoring for Trikafta (elexacaftor/tezacaftor/ivacaftor) in a cystic fibrosis patient aged ≥12 years with at least one F508del mutation?

Trikafta (Elexacaftor/Tezacaftor/Ivacaftor) for Cystic Fibrosis

Trikafta is indicated for CF patients aged ≥2 years with at least one F508del mutation in the CFTR gene, dosed as two tablets (each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning and one tablet of ivacaftor 150 mg in the evening for patients ≥12 years, taken with fat-containing food. 1

Indications and Patient Selection

• Trikafta is approved for patients aged ≥2 years with at least one F508del mutation or a mutation responsive based on clinical and/or in vitro data. 1
• If the patient's genotype is unknown, an FDA-cleared CF mutation test must be used to confirm the presence of at least one indicated mutation. 1
• This represents a major advance, as approximately 90% of CF patients now have access to CFTR modulator therapy, though roughly 10% remain ineligible due to their specific genetic mutations. 2, 3

Dosing Regimen for Patients ≥12 Years

• Morning dose: Two tablets, each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg 1
• Evening dose: One tablet of ivacaftor 150 mg 1
• All doses must be taken with fat-containing food to optimize absorption. 1

Hepatic Dosing Adjustments

• Trikafta should NOT be used in patients with severe hepatic impairment (Child-Pugh Class C). 1
• Trikafta is NOT recommended in patients with moderate hepatic impairment (Child-Pugh Class B) unless the benefit outweighs the risk; if used, reduce the dose and monitor liver function tests closely. 1

Critical Safety Monitoring: Boxed Warning for Liver Injury

The FDA has issued a boxed warning for drug-induced liver injury and liver failure, including cases requiring transplantation and resulting in death. 1

Mandatory Liver Function Monitoring Protocol:

• Baseline: Obtain ALT, AST, alkaline phosphatase, and bilirubin before initiating therapy. 1
• First 6 months: Monitor liver function tests MONTHLY. 1
• Months 7-18: Monitor liver function tests every 3 MONTHS. 1
• After 18 months: Monitor liver function tests at least ANNUALLY. 1

Management of Elevated Liver Enzymes:

• Interrupt Trikafta immediately for significant elevations in liver function tests or any signs/symptoms of liver injury. 1
• Follow patients closely with clinical and laboratory monitoring until abnormalities resolve. 1
• Resume Trikafta only if abnormalities resolve AND only if the benefit is expected to outweigh the risk. 1

Drug Interactions Requiring Dose Adjustments

• Trikafta is metabolized via CYP3A4, requiring careful monitoring for drug interactions. 4
• Strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole) require dose reduction of Trikafta. 1
• Strong CYP3A4 inducers (e.g., rifampin, phenytoin) significantly reduce Trikafta levels and should be avoided. 1

Clinical Efficacy: Superior to Previous Therapies

Trikafta demonstrates substantial superiority over tezacaftor-ivacaftor alone in F508del homozygous patients, with a mean improvement in percent predicted FEV1 of 10.2 percentage points greater than tezacaftor-ivacaftor. 5, 6

Key Efficacy Outcomes:

• Lung function: Mean increase of 11.2 percentage points in percent predicted FEV1 compared to 1.0 percentage points with tezacaftor-ivacaftor alone (p<0.0001). 6
• Quality of life: CFQ-R respiratory domain score increased by 17.1 points with Trikafta versus 1.2 points with tezacaftor-ivacaftor (treatment difference 15.9 points, p<0.0001). 6
• CFTR function: Sweat chloride concentration decreased by 46.2 mmol/L with Trikafta versus 3.4 mmol/L with tezacaftor-ivacaftor (p<0.0001). 6
• Exacerbations: Pulmonary exacerbation rate reduced by 35% compared to placebo in earlier studies. 7

Common Adverse Events

• Most common adverse events include headache and rash, typically mild to moderate in severity. 2, 3
• Serious adverse events occurred in only 6% of patients on Trikafta versus 16% on tezacaftor-ivacaftor. 6
• Discontinuation due to adverse events is rare (2.9% in clinical trials). 7
• One case of anxiety/depression led to discontinuation in the Trikafta group. 6

De-escalation of Supportive Therapies

After initiating Trikafta, consider discontinuing inhaled anticholinergics and beta-agonists, leukotriene modifiers, N-acetylcysteine, glutathione, and oral antistaphylococcal antibiotics, as Trikafta addresses the underlying CFTR defect. 5

Therapies to Continue:

• Airway clearance therapy should be continued and intensified during respiratory infections. 8
• Chronic azithromycin for patients without Pseudomonas aeruginosa to reduce exacerbations. 8, 4
• Inhaled tobramycin or aztreonam for patients with persistent P. aeruginosa. 4
• Dornase alfa and hypertonic saline may still provide benefit in some patients. 8, 4

Critical Pitfalls to Avoid

• Never use Trikafta in patients with severe hepatic impairment (Child-Pugh Class C)—this is an absolute contraindication. 1
• Do not skip monthly liver function monitoring during the first 6 months—liver failure has been fatal. 1
• Do not assume all CF patients are eligible—confirm F508del mutation or responsive mutation with FDA-cleared testing. 1
• Do not administer without fat-containing food—absorption is significantly reduced. 1
• Do not overlook CYP3A4 drug interactions—these can lead to toxicity or treatment failure. 1